Abilify Maintena

Abilify Maintena

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of aripiprazole in the treatment of schizophrenia is unknown. However, the efficacy of aripiprazole may be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.

Alcohol

There was no significant difference between oral aripiprazole co-administered with ethanol and placebo co-administered with ethanol on performance of gross motor skills or stimulus response in healthy subjects. As with most psychoactive medications, patients should be advised to avoid alcohol while taking ABILIFY MAINTENA.

Pharmacokinetics

ABILIFY MAINTENA activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D2 receptors similar to the parent drug and represents about 29% of the parent drug exposure in plasma.

Aripiprazole absorption into the systemic circulation is slow and prolonged following intramuscular injection due to low solubility of aripiprazole particles. Following a single intramuscular dose, the plasma concentrations of aripiprazole gradually rise to reach maximum plasma concentrations at a median Tmax of 5-7 days. The mean aripiprazole terminal elimination half-life was 29.9 days and 46.5 days after every 4-week injection of ABILIFY MAINTENA 300 mg and 400 mg, respectively, and steady state concentrations were attained by the fourth dose. Approximate dose-proportional increases in aripiprazole and dehydro-aripiprazole concentrations and AUC parameters were observed after every four week ABILIFY MAINTENA injections of 300 mg and 400 mg.

Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation.

Drug Interaction Studies

No specific drug interaction studies have been performed with ABILIFY MAINTENA. The information below is obtained from studies with oral aripiprazole.

Potential for Other Drugs to Affect ABILIFY MAINTENA

Ketoconazole and Other Strong CYP3A4 Inhibitors

Co-administration of ketoconazole (200 mg/day for 14 days) with a 15 mg single oral dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied.

Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Quinidine and Other Strong CYP2D6 Inhibitors

Co-administration of a 10 mg single oral dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Carbamazepine and Other CYP3A4 Inducers

Co-administration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with oral aripiprazole (30 mg/day) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Valproate

When valproate (500 mg/day-1500 mg/day) and oral aripiprazole (30 mg/day) were coadministered, at steady-state the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with valproate.

Lithium

A pharmacokinetic interaction of ABILIFY MAINTENA with lithium is unlikely because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine. Co-administration of therapeutic doses of lithium (1200 mg/day-1800 mg/day) for 21 days with oral aripiprazole (30 mg/day) did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax and AUC increased by less than 20%). No dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with lithium.

Potential for ABILIFY MAINTENA to Affect Other Drugs

Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In vivo studies, 10 mg/day to 30 mg/day doses of oral aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydroaripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro.

No effect of oral aripiprazole was seen on the pharmacokinetics of lithium or valproate.

Valproate

When oral aripiprazole (30 mg/day) and valproate (1000 mg/day) were co-administered, at steady state there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with ABILIFY MAINTENA.

Lithium

Co-administration of oral aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with ABILIFY MAINTENA.

Dextromethorphan

Oral aripiprazole at doses of 10 mg/day to 30 mg/day for 14 days had no effect on dextromethorphan's O-dealkylation to its major metabolite, dextrorphan, a pathway dependent on CYP2D6 activity. Oral aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methoxymorphinan, a pathway dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with ABILIFY MAINTENA.

Warfarin

Oral aripiprazole 10 mg/day for 14 days had no effect on the pharmacokinetics of Rwarfarin and S-warfarin or on the pharmacodynamic end-point of International Normalized Ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with ABILIFY MAINTENA.

Omeprazole

Oral aripiprazole 10 mg/day for 15 days had no effect on the pharmacokinetics of a single 20 mg dose of omeprazole, a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with ABILIFY MAINTENA.

Escitalopram

Co-administration of 10 mg/day doses of oral aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of 10 mg/day escitalopram, a substrate of CYP2C19 and CYP3A4. No dosage adjustment of escitalopram is required when ABILIFY MAINTENA is added to escitalopram.

Venlafaxine

Co-administration of 10 mg/day to 20 mg/day doses of oral aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of venlafaxine and Odesmethylvenafaxine following 75 mg/day venlafaxine XR, a CYP2D6 substrate. No dosage adjustment of venlafaxine is required when ABILIFY MAINTENA is added to venlafaxine.

Specific Population Studies

No specific pharmacokinetic studies have been performed with ABILIFY MAINTENA in specific populations. All the information is obtained from studies with oral aripiprazole.

CYP2D6 Poor Metabolizers

Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs). People who are not PMs are classified as extensive metabolizers (EMs). Laboratory tests are available to identify CYP2D6 PMs. PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. The mean elimination half-lives for aripiprazole are about 75 and 146 hours in EMs and PMs, respectively. Hence, the recommended dosage of ABILIFY MAINTENA is lower [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Aripiprazole does not inhibit or induce the CYP2D6 pathway.

Gender

Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30% to 40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight (25%) between men and women. No dosage adjustment of ABILIFY MAINTENA is recommended based on gender.

Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of aripiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of aripiprazole. No dosage adjustment of ABILIFY MAINTENA is recommended based on race.

Smoking

Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics of aripiprazole. Consistent with these in vitro results, population pharmacokinetic evaluation did not reveal any significant pharmacokinetic differences between smokers and nonsmokers. No dosage adjustment of ABILIFY MAINTENA is recommended based on smoking status.

Renal Impairment

In patients with severe renal impairment (creatinine clearance < 30 mL/min), Cmax of oral aripiprazole (given in a single dose of oral 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole and dehydroaripiprazole is less than 1% of the dose. No dosage adjustment of ABILIFY MAINTENA is required for doses in subjects with renal impairment.

Hepatic Impairment

In a single-dose trial (15 mg of oral aripiprazole) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild hepatic impairment, increased 8% in moderate hepatic impairment, and decreased 20% in severe hepatic impairment. None of these differences would require dose adjustment of ABILIFY MAINTENA.

Animal Toxicity and/or Pharmacology

Oral Aripiprazole

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg. The 40 mg/kg and 60 mg/kg doses are 13 times and 19 times the oral maximum recommended human dose (MRHD) of 30 mg/day based on mg/m² body surface area and 7 times to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

Intramuscular Aripiprazole

The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. With intramuscular injection, however, injectionsite tissue reactions are observed that consist of localized inflammation, swelling, scabbing and foreign-body reactions to deposited drug. These effects gradually resolved with discontinuation of dosing.

After 26 weeks of treatment in rats, the no-observed-adverse-effect level (NOAEL) was 50 mg/kg in male rats and 100 mg/kg in female rats, which are approximately 1 and 2 times, respectively, the maximum recommended human 400 mg dose of aripiprazole extended-release injectable suspension on a mg/m² body surface area. At the NOAEL in rats, the AUC7d values were 14.4 μg•h/mL in males and 104.1 μg•h/mL in females. In dogs at 52 weeks of treatment at the NOAEL of 40 mg/kg, which is approximately 3 times the MRHD (400 mg) on a mg/m² body surface area, the AUC7d values were approximately 59 μg•h/mL in males and 44 μg•h/mL in females. In patients at the MRHD of 400 mg, the AUCτ (0-28 days) was 163 μg•h/mL. For comparison to this human AUC, extrapolating the animal AUC7d values to an AUC28d results in AUC28d values of approximately 58 and 416 μg•h/mL for male and female rats, respectively, and 236 and 175 μg•h/mL for male and female dogs, respectively.

Clinical Studies

The efficacy of ABILIFY MAINTENA in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of ABILIFY MAINTENA in maintaining symptomatic control in schizophrenia was established in a randomized-withdrawal, double-blind, placebo-controlled, trial in adult patients who met DSM-IV-TR criteria for schizophrenia and who were being treated with at least one antipsychotic medication. Patients had at least a 3 year history of illness and a history of relapse or symptom exacerbation when not receiving antipsychotic treatment. Clinical ratings during this trial included:

  • The Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210.
  • The Clinical Global Impression-Severity (CGI-S) scale. The CGI-S rates the severity of mental illness on a scale of 1 (normal) to 7 (among the most extremely ill) based on the total clinical experience of the rater in treating patients with schizophrenia.
  • The Clinical Global Impression-Improvement (CGI-I) scale. The CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition.
  • The Clinical Global Impression- Severity of Suicide (CGI-SS) scale, which is comprised of 2 parts: Part 1 rates the severity of suicidal thoughts and behavior on a scale of 1 (not at all suicidal) to 5 (attempted suicide) based on the most severe level in the last 7 days from all information available to the rater and Part 2 rates the change from baseline in suicidal thoughts and behavior on a scale of 1 (very much improved) to 7 (very much worse).

This trial included:

  • A 4-6 week open-label, oral conversion phase for patients on antipsychotic medications other than aripiprazole. A total of 633 patients entered this phase.
  • An open-label, oral aripiprazole stabilization phase (target dose of 10 mg to 30 mg once daily). A total of 710 patients entered this phase. Patients were 18 to 60 years old (mean 40 years) and 60% were male. The mean PANSS total score was 66 (range 33 to 124). The mean CGI-S score was 3.5 (mildly to moderately ill). Prior to the next phase, stabilization was required. Stabilization was defined as having all of the following for four consecutive weeks: an outpatient status, PANSS total score ≤ 80, CGI-S ≤ 4 (moderately ill), and CGI-SS score ≤ 2 (mildly suicidal) on Part 1 and ≤ 5 (minimally worsened) on Part 2; and a score of ≤ 4 on each of the following PANSS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content.
  • A minimum 12-week uncontrolled, single-blind ABILIFY MAINTENA stabilization phase (treatment with 400 mg of ABILIFY MAINTENA given every 4 weeks in conjunction with oral aripiprazole [10 mg to 20 mg/day] for the first 2 weeks). The dose of ABILIFY MAINTENA may have been decreased to 300 mg due to adverse reactions. A total of 576 patients entered this phase. The mean PANSS total score was 59 (range 30 to 80) and the mean CGI-S score was 3.2 (mildly ill). Prior to the next phase, stabilization was required (see above for the definition of stabilization) for 12 consecutive weeks.
  • A double-blind, placebo-controlled randomized-withdrawal phase to observe for relapse (defined below). A total of 403 patients were randomized 2:1 to the same dose of ABILIFY MAINTENA they were receiving at the end of the stabilization phase, (400 mg or 300 mg administered once every 4 weeks) or placebo. Patients had a mean PANSS total score of 55 (range 31 to 80) and a CGI-S score of 2.9 (mildly ill) at entry. The dose could be adjusted up and down or down and up within the range of 300 to 400 mg on a one time basis.

The primary efficacy endpoint was time from randomization to relapse. Relapse was defined as the first occurrence of one or more of the following criteria:

  1. CGI-I of ≥ 5 (minimally worse) and
    1. an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 with an absolute increase of ≥ 2 on that specific item since randomization or
    2. an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 and an absolute increase ≥ 4 on the combined four PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) since randomization
  2. Hospitalization due to worsening of psychotic symptoms (including partial hospitalization), but excluding hospitalization for psychosocial reasons
  3. CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2, or
  4. Violent behavior resulting in clinically significant self-injury, injury to another person, or property damage.

A pre-planned interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the ABILIFY MAINTENA group compared to placebotreated patients and the trial was subsequently terminated early because maintenance of efficacy was demonstrated. The final analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the ABILIFY MAINTENA group than compared to placebo-treated patients (log-rank test p < 0.0001). The Kaplan-Meier curves of the time from randomization to relapse during the double-blind treatment phase for ABILIFY MAINTENA and placebo groups are shown in Figure 11.

Figure 11: Time to Relapse1

Time to Relapse - Illustration

1 This figure is based on a total of 80 relapse events

The key secondary efficacy endpoint, percentage of subjects meeting the exacerbation of psychotic symptoms/ relapse criteria, was statistically significantly lower in patients randomized to the ABILIFY MAINTENA group (10%) than in the placebo group (40%).

Last reviewed on RxList: 3/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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